The gradual development of facial wrinkles, whether fine surface lines or deeper creases and folds, is an early sign of accumulated skin damage and skin aging, which may be intrinsic and/or caused or accelerated by external factors. For example, premature aging and wrinkling of the skin may be accelerated by excessive exposure to the sun and other damaging elements, overactive facial expression muscles, frequent use of tobacco products, poor nutrition, or skin disorders. Fine surface wrinkles that progress to deeper creases, deepening facial expression due to repeated skin folding, and deep folds which develop with one's maturity are visible changes which may combine to portray a less desirable appearance. Several invasive techniques are available in which substances are injected or implanted in the area of the skin which either temporarily weaken the muscles or act as skin volume fillers. However, invasive techniques are often risky and require the supervision or assistance of a physician, which can be inconvenient and costly, and non-invasive treatments have historically met with only minimal success. Regardless of the cause of facial creases or folds, safe and effective treatments for reduction or elimination of these problems have been exceedingly difficult to achieve.
Thornfeldt et al. recommended that skin care regimens using active ingredients that are recommended by physicians who treat mucocutaneous conditions including aging should become more focused on reversing and preventing chronic inflammation. Thornfeldt reported that chronic inflammation appears strongly linked to many preventable and treatable skin diseases and conditions such as visible skin aging. Thornfeldt stated that mucocutaneous inflammation as the final common pathway of many systemic and mucocutaneous diseases including extrinsic aging has been established at the molecular and cellular levels. (see Thornfeldt, C R (2008) J. Cosmet. Dermatol. 7:78-82).
Bissett et al. reported that albino hairless mice exposed chronically to suberythemal doses of ultraviolet (UV) radiation displayed an increase in dermal cellularity, including inflammatory cells. In one experiment, Bissett observed that topical hydrocortisone, ibuprofen, and naproxen protected against UVB radiation-induced visible wrinkling, tumor formation, and histological alternations in albino hairless mice. In another experiment, Bissett observed that hydrocortisone and naproxen were effective against UVA radiation-induced visible skin sagging and histological alterations in albino hairless mice. The investigators hypothesized that this data suggested role for inflammation in chronic photodamage. (see Bissett, et al. (1990) Photodermatol. Photoimmunol. Photomed. 7:153-8).
Calcineurin is a protein phosphatase involved in the activation of Nuclear factor of activated T cells (“NFAT”), a transcription factor. Activation of NFAT transcription factor stimulates T cells involved in calcium trafficking and inflammatory responses. Expression of calcineurin in skin increases intrinsically over time with age.
Topical calcineurin inhibitors, such as a tacrolimus ointment commercially available as PROTOPIC®, have been used to treat atopic dermatitis, which is an eczematous skin disease that has typically been treated with topical steroids. A tacrolimus ointment has been reported to inhibit calcineurin, which results in suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release. (see, e.g., Bekersky et al, 2001, J. Am. Acad. Dermatol. 441:S17-S27). Furue et al. reported that tacrolimus ointment was used as a first-line treatment for the inflammation of atopic dermatitis. (see e.g. Furue, et al. (2006) Dermatol. Ther. 19:118-26). Another commercially available calcineurin inhibitor is pimecrolimus, which is commercially available in a cream as ELIDEL®.
Melicope hayesii is a shrub in the Melicope genus and the Rutaceae family that may be found in the wild on the north coast of New South Wales (NSW), Australia. The Melicope plant genus includes about 150 different species of shrubs and trees in the family, which may be found in western Hawaii, tropical regions of Asia, Australia and New Zealand. Plants in the Melicope genus are commonly referred to as “Corkwood” or “Doughwood” in Australia and as “Alani” in Hawaii.
There remains a need for cosmetic compositions which reduce signs of aging. It is therefore an object of the invention to provide new compositions and methods for inhibiting calcineurin activity. It is a further object of the invention to improve the overall appearance of skin, including treating, reversing, and/or preventing signs of aging, such as skin wrinkles, by inhibiting calcineurin activity with new cosmetic compositions.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.